Sofosbuvir is a prodrug used for the treatment of hepatitis C.
Hepatitis C is an infectious disease caused by Hepatitis C virus (HCV) which affects primarily the liver. The infection is often asymptomatic but its chronic infection can lead to the scarring of the liver and finally to cirrhosis, which is generally apparent after many years. In some cases the liver cirrhosis can develop liver failure, liver cancer, esophageal and gastric varices. HCV is transmitted primarily by direct contact with infected blood, often caused by intravenous drug use, poorly sterilized equipment and blood transfusions.
Hepatitis C virus causes a chronic infection in 50-80% of the peoples who are infected with, among them about 40-80% is treated. In general, the pharmacological treatment is recommended in patients with liver changes caused by virus; the reference treatment is a combination of pegylated interferon alpha and ribavirin to be taken for a period of 24 or 48 weeks, depending on the HCV virus genotype. It is observed that this treatment leads to improvements in 50-60% of cases. In phenotypes which are more difficult to be treated these two drugs are used in combination with boceprevir and telaprevir bringing the cure rate from 40% to 70%. The side effects of the treatment are frequent: half patients have flu like symptoms and one third has emotional problems, moreover the treatment carried out during the first six months is more effective than once hepatitis C has become chronic. Sofosbuvir is a drug for the treatment of hepatitis C, approved at the beginning of the year by EMA, it is taken orally and acts with a direct mechanism of action on the life cycle of the virus abolishing its replication as being a prodrug inhibitor pan-genotype of RNA polymerase NS5B RNA-dependent of HCV, it can be incorporated into HCV RNA NS5B polymerase and acts as a chain terminator.
Sofosbuvir has moreover shown a reduced number of complications of the liver disease and a reduced number of adverse effects than patients undergoing other treatments.
Sofosbuvir is a compound of formula (I)

chemically known as isopropyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidine-1-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydrofuran-2-yl]methoxy-phenoxy-phosphoryl]-aminopropanoate, marketed as Sovaldi® and described in U.S. Pat. No. 8,563,530.
Some polymorphic forms of Sofosbuvir are known in the literature.
U.S. Pat. No. 8,618,076 describes crystalline, hydrated and solvated forms of Sofosbuvir, named as Form 1 (crystalline), Form 2 (crystalline), Form 3 (chloroform solvate), Form 4 (hydrate), Form 5 (crystalline) and Form 6 (crystalline) and describes also two amorphous forms.
Polyphormism is the property of the molecules to assume more than one crystalline or amorphous form in their solid state. Some substances are know to exist in only one crystalline or amorphous form; others indeed can have two or more crystalline forms. Polymorphs are different solids with the same molecular formula but with different physical properties that can be advantageous or disadvantageous compared with the other polymorphic forms of the same family.
The morphology of organo-chemical active ingredients is important for their pharmaco chemical development. A crystalline form, compared to other crystalline forms, can have many advantages. A suitable process for a crystalline form can give to active ingredient's manufacturers several advantages, such as, the use of steps or solvents cheap or with a low environmental impact, higher yields and higher purity of the desired product.
The polymorphism, the number of crystalline forms of an organo-chemical compound, their stability and their behavior in a living organism are never predictable. The different polymorphs of a compound have different energies of the crystal lattice and show in this way, different physical properties of the solid state (such as shape, density, melting point, colour, stability, dissolution rate, ease of grinding, granulation etc.). In polymorphism, these morphological differences can have drastic effects on the flowability of the ground solid (the flowability regards the easiness whereby the material is treated during the processing into a pharmaceutical product), on shipping and storage stability of different forms of administration, on the ability to produce different forms of administration, on solubility in polar or non polar, protic or aprotic solvents, on solubility in aqueous solutions, on solubility in gastric juices, on blood solubility and finally on bioavailability.
The dissolution rate of an active ingredient in the gastric fluid of a patient can have therapeutical effects because it determines the maximum concentration that an active ingredient can reach in the blood by oral administration. Other important properties of polymorphic forms affect the easiness of transforming the active ingredient form in pharmaceutical dosages, on the flowability of a powder or a granulate form and the surface properties that determine if the crystals of the form will stick each other once compressed in a tablet.
A polymorphic form can have a different thermic behavior compared to an amorphous form or any other polymorphic form. Thermic behavior can be measured in laboratory through techniques such as capillary melting point and differential scanning calorimetry (DSC) and can be used to distinguish various polymorphic forms. A polymorphic form can have different spectroscopical properties that can be detected trough the X-Ray Powder diffraction (XRPD).
The discovery of new polymorphic forms of a pharmaceutical compound gives another possibility to improve the characteristics of said product. An expert of pharmaceutical techniques extends his/her knowledge of forms useful for the development of a pharmaceutical form with a targeted release profile or with other characteristics such as fluidity and dissolution rate in aqueous liquids.